Process for the manufacture of substituted tetralones



March 17, 1953 c. GROB 2,632,024

PROCESS FOR; THE MANUFACTURE OF SUBSTITUTED TETRALONES Filed Sept. 25,1949 I II NH2 S03 a 0 OH 004 i: j ocH Y ocH a ccu ocH

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Zoe/2221" QI' ZGIWJ I UNITED STATES PATENT OFFICE PROCESS FOR THEMANUFACTURE OF SUBSTITUTED TETRALONES Cyril Grob, Basel, Switzerland,assignor to 01'- ganon Inc., Orange, N. J a corporation of New JerseyApplication September 23, 1949,Serial No. 117,485. In the NetherlandsOctober 2, 1948 8 Claims.

' The invention relates to a process for the manufacture of substitutedtetralones.

Tetralones can be derived from tetraline in which an oxygen atom isattached to the hydrogenated nucleus. :1. and [i tetralones aredistinguished in the same manner as a and B substituted naphthalenes aredistinguished.

The invention relates particularly to the manufacture of a substituted 5tetralone, namely the dimethoxy-5.8 tetralone-2. To this appertains theFormula VI of the annexed drawing. This substance is an importantintermediate product in the synthesis of steroids. In the rest of thisspecification this substance will be spoken of, but it will be clearthat within the scope of the invention one is not limited tomethoxy-groups but that also other alkyloxy groups or acyloxy groups maybe present instead of the methoxy group.

For this purpose e. g. methoxy-G naphthoquinone-1.4 (III) is used as astarting material. This substance can e. g. be prepared from Cleveacid(I), this is converted in known manner into methoxy-6 naphthyl-l amine(II), as described a. o. by A. Butenandt and G. Schramm, Ber. 68, 2085(1935) or W. E. Bachmann, W. Cole and A. L. Wi-lds, J. A. C. S. 62, 824(1940). Analogous to the method of H. E. Fierz-David, L. Blangey and W.Von Kranichfeld (Helv. Chim. Acta 30, 832 (1947)) (II) is converted intomethoxy-S naphthoquinone-L4 (III).

The methoxy-6 naphthoquinone-1.4 (III) is reduced with Raney nickel inbenzene to dihydroxy-1.4 methoxy-G naphthalene (IV) which by methylation is converted in known manner into trimethoxy-1.4.6. naphthalene(V). The conversion of III to IV by reduction with Raney nickel inbenzene was not self-evident. It was already known, it is true, toreduce dimethy1-2.3 dimeth oxy-6.7 naphthoquinone-L4 with Raney nickelin methanol (J. A. C. S. 66, 1315 (1944)) but here the reduction of IIIwith Raney nickel in methanol, ethanol or ether does not yield asatisfying result; on the contrary this reduction surprisingly succeedssmoothly in benzene. When further e. g. III is reduced with zinc dust inglacial acetic acid the diacetate of dihydroxy-1.4 methoxy-6 naphthaleneis smoothly obtained but it is not possible to convert this substanceinto IV.

The conversion of trimethoxy-1.4.6 naphthalene (V) into the desiredfinal product: dimethoxy-5.8 tetralone-2 (VI) is performed by sodium inalcohol or sodium and alcohol in liquid ammonia via the enol compound(vide Cornforth, Cornforth and Robinson, Soc. 1942, 689; Soc. 1946, 676;Birch, Soc. 1944, 430).

The invention must be seen in the indication of the entire process'frome. g. methoxy-S naphthoquinone-L4 to the substituted tetraloneinpartially known, partially,- however, unknown manners. What was saidfor the-meth'oxy com-- pounds applies in full to all naphthoquinones-L4substituted by an alkoxy or an acyloxy group in the 5 or 6 position.

EXAMPLE 1.5 g. of the methoxy-G naphthoquinone-L4 (M. P. 134-135" C.)obtained in known manner from Cleve-acid are dissolved in 'cm. of purebenzene and hydrogenated during 2 hours withhas a melting point of148-150 C. (by sublimaetion yellow needles can be obtained .herefromwith a melting point of 89-90 0.; probably there are here twomodifications of the same, substance). 1.5 g. of .crude methoXy-G'naphthohydroquinone-L4 are obtained which is methylated;

in known manner, e. g. according to O. Fischer and C. Bauer, J. pr.Chem. II, 94', 2' (1917). The trimethoxy-1.4.6. naphthalene obtained inthis manner distills under a pressure of 0.2 mm. at -141" C. The picrateof this compound melts at 148-149 C.

A. Reduction withsodium and alcohol 0.7 g. of. the above obtainedtrimethoxy-1.4.6' naphthalene are dissolved in 8 cm. of absolute alcoholand within 10 minutes 1.1 g. of finely cut sodium metal is thrown inthrough the reflux cooler. The orange colored liquid is heated forapproximately 30 minutes in a bath of l15-120 C.; the sodium then hasdisappeared. The solution is cooled, diluted with 10 cm. of water andimmediately 10 cm. of strong hydrochloric acid are added. The solutionis heated on the waterbath for 20 minutes and now and then shaken, thealcoho1 is evaporated in vacuo, some water is added and the product issubjected four times to extraction by means of ether. The ether solutionis three times washed with water, evaporated to mm. and shaken with 5cm. of a freshly prepared concentrated sodiumbisulfite solution. After 5minutes a White crystalline precipitate results which after some time issucked off and washed with ether. The bisulfite compound is decomposedin the usual manner, a yield of 60% of the desired tetralone beingobtained with a melting point of 89-95 C. By molecular sublimationdimethoXy-5.8 tetralone-2 with a melting point of 99-100 C. is obtained.This substance dissolves Well in benzene, in warm alcohol and ether andpoorly in petroleumether. The semicarbazone has a melting point of20320'7 C., it dissolves well in chloroform, methylenechloride, warmmethanol and acetone.

B. Reduction with sodium and alcohol in liquid ammonia 0.55 g. oftrimethoxy-l.4.6 naphthalene are dissolved in 0.6 cm. of alcohol andwhile cooling with Dry Ice yet cm. of liquid ammonia are added. Whileshaking 500 mg. of sodium are added and the solution is left alone whilecooling still for 5 hours after the blue color having disappeared. Atroom temperature the ammonia is allowed to evaporate and the residuesare removed-in a vacuum. Thereupon some alcohol is added, 5 cm. of waterandfinall 5 cm. of strong hydrochloric acid. The reaction mixture isthen further worked up as indicated under A.

When it is tried to carry out the above described reduction of methoxy-Gnaphthoquinone- 1.4 with Raney nickel in ether solution one does notobtain the desired product. When it is desired to convert the methoXy-6naphthoquinone- 1.4 via the diacetate into the hydroquinone, oneencounters the diificulty that from the diacetate only unimportantquantities of the desired final product can be obtained.

Having now particularly described and ascertained the nature of my saidinvention and in what manner same is to be performed What I claim is:

1. As a new compound, dialkoxy-SB tetralone-2.

2. As a new compound, dimethoxy-5.8 tetralone-2.

3. The method of preparing dialkoxy-5,8- tetralone-2 compoundscomprising hydrogenating an alkoxy-6-naphthoquinone-1,4 compound inbenzene solution in the presence of Raney nickel to analkoxy-6-naphthohydroquinone-l,4 compound, alkylating the hydroxylgroups in said naphthohydroquinone compound, and reducing the resultingtrialkoxy-1,4,6-naphthalene compound by means of an alkali metal andalcohol to the corresponding dialkoxy-5,8-tetralone-2 compound.

4. The method of preparing dimethoxy-5,8- tetralone-2, comprisinghydrogenating methoxy- 6-naphthoquinone-1,4 in benzene solution in thepresence of Raney nickel to methoxy-6-naphthohydroquinone-1,4,methylating the hydroxyl groups in said naphthohydroquinone compound,and reducing the resulting trimethoxy-1,4,6- naphthalene by means of analkali metal and alcohol to the corresponding dimethoxy-5,8-tetralone-2.

5. The method according to claim 3, wherein the reduction by means of analkali metal and alcohol is carried out in liquid ammonia.

6. The method according to claim 4, wherein the reduction by means of analkali metal and alcohol is carried out in liquid ammonia.

7. In a method of preparing dialkoXy-5,8- tetralone-2 compounds byhydrogenating an alkoxy-fi-naphthoquinone-1,4 compound to an alkoxy 6naphthohydroquinone-L4 compound, alkylating the hydroxyl groups in saidnaphthohydroquinone compound, and reducing the resultingtrialkoxy-l,4,6-naphthalene compounds by means of an alkali metal andalcohol to the corresponding dialkoxy 5,8 tetralone 2 compound, the stepcomprising hydrogenating said alkoxy-G-naphthoquinone-1,4 compound inbenzene solution in the presence of Raney nickel.

8. In a method of preparing dimethoxy-5,8- tetralone-2 by hydrogenatingmethoxy-G-naphthoquinone-1,4 to methoxy-fi-naphthohydroquinone-1,4,methylating the hydroxyl groups in said naphthohydroquinone, andreducing the resulting trimethoxy-l,4,6-naphthalene by means of analkali metal and alcohol to thecorresponding dimethoXy-5,8-tetralone-2,the step comprising hydrogenating said methoxy-G-naphthoquinone1,4 inbenzene solution in the presence of Raney nickel.

CYRIL GROB.

REFERENCES CITED The following references are of record in the file ofthis patent:

UNITED STATES PATENTS Number Name Date 1,967,862 Carothers et a1. July24, 1934 FOREIGN PATENTS Number Country Date 397,150 Germany June 14,1924 OTHER REFERENCES $00., 1942 vol., pp.

800., 1946 vol., pp.

Acta, vol. 31, pp.

Acta, V01. 31, pp.

1. AS A NEW COMPOUND, DIALKOXY-5.8 TETRALONE-2. 